EP0275404A1 - Compositions d'analogue de LHRH - Google Patents

Compositions d'analogue de LHRH Download PDF

Info

Publication number
EP0275404A1
EP0275404A1 EP87117226A EP87117226A EP0275404A1 EP 0275404 A1 EP0275404 A1 EP 0275404A1 EP 87117226 A EP87117226 A EP 87117226A EP 87117226 A EP87117226 A EP 87117226A EP 0275404 A1 EP0275404 A1 EP 0275404A1
Authority
EP
European Patent Office
Prior art keywords
formulation
propellant
lhrh analog
lhrh
leuprolide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP87117226A
Other languages
German (de)
English (en)
Other versions
EP0275404B1 (fr
Inventor
Akwete L. Adjei
James W. Kesterson
Edwin S. Johnson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US06/934,874 external-priority patent/US4851211A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to EP92111535A priority Critical patent/EP0510731B1/fr
Priority to AT87117226T priority patent/ATE88341T1/de
Publication of EP0275404A1 publication Critical patent/EP0275404A1/fr
Application granted granted Critical
Publication of EP0275404B1 publication Critical patent/EP0275404B1/fr
Priority to GR960401850T priority patent/GR3020482T3/el
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides

Definitions

  • the invention relates to novel formulations comprising LHRH (luteinizing hormone releasing hormone) analogs and, more particularly, to LHRH analog aerosol formulations.
  • LHRH luteinizing hormone releasing hormone
  • Polypeptides and LHRH analogs in particular are historically administered parenterally because they are poorly absorbed by biological membranes due to their large molecular size and polarity, enzymatic degradation and deactivation by proteases enroute to the circulatory system.
  • leuprolide is a polar nonapeptide with three ionizable sites, namely the imidazolyl nitrogen of histidine with pKa approximately 6.0, the phenolic hydroxyl of tyrosine with pKa approximately 10.0, and the guanidine nitrogen of arginine with pKa approximately 13.0. Since the guanidine nitrogen is extremely basic, this nonapeptide as synthesized exists in the protonated form and is generally associated with at least one mole of acetic acid. Leuprolide, therefore, exists as an acetate salt, which is highly hydrophilic.
  • LHRH analogs are practically insoluble in fluorocarbons.
  • solubility of leuprolide approaches 3 mg/ml which is not satisfactory due to dose requirements.
  • This solubility estimate is not significantly affected by the presence of nonionic surfactants because, in part, of solubility and dielectric limitations of such surfactants.
  • ethyl alcohol and water experimental results showed equilibrium solubility of leuprolide to approach 5 mg/ml which is still unacceptable.
  • a gel-like mass forms resulting in a colloidal dispersion that does not clear at room temperature for up to one month.
  • water concentrations of 10% or greater a complete phase separation occurs making a homogeneous formulation impractical and renders aerosolization impractical.
  • Preparing suspension aerosols requires micronization of the drug prior to manufacture of the aerosol. This process involves mechanical breakup of the powder using grinding or milling equipment to reduce drug particle size to below 10 microns which is essential for pulmonary deposition of the aerosol. Generally, this milling process results in significant exposure of the drug to the surrounding environment as well as up to 20% loss of the drug.
  • the airborne LHRH analog particles can cause safety and health hazards if precautionary measures are not taken.
  • solution aerosol formulations for administration of LHRH analogs comprise:
  • the suspension aerosol formulations for administration of LHRH analogs comprise:
  • the preferred suspension formulation of the invention is as follows:
  • the solution aerosol composition for administration of LHRH analogs by inhalation comprises:
  • the suspension aerosol composition for administration of LHRH analogs comprises:
  • % w/w refers to weight of ingredient per weight of formulation multiplied by 100.
  • LHRH analog refers to octapeptides, nonapeptides and decapeptides including but not limited to leuprolide and D-amino acid analogs of LHRH. More particularly, LHRH analogs in addition to leuprolide (U.S. Patent No. 4,005,063) which can be formulated in accordance with the invention include those which are described in U.S. Patent Nos. 3,853,837, 3,972,859, 4,008,209, 4,024,248 (buserilin) 4,089,946 (lutrelin), 4,100,274 (goserelin), 4,234,571 (nafarelin), 4,490,291, and also includes histrelin.
  • leuprolide or “leuprolide acetate” refers to a nonapeptide, 5-Oxo-L-prolyl-L-histidyl-L-tryptophanyl-L-seryl-L-­tyrosyl-D-leucyl-L-leucyl-L-arginyl-L-prolylethylamide acetate with the structure:
  • surfactant refers to nonionic surfactants including but not limited to mono and diglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol esters, polyoxyethylene acids, polyoxyethylene alcohols and polyoxyethylene adducts.
  • lipophilic counterion refers to organic acids or their salts with pka sufficiently low to render them ionizable at the product pH and includes but is not limited to alkyl (C5-C12) sulfonic acids and salts thereof, palmitates, dioctylsulfosuccinate and its congeners, stearates and salicylates.
  • propellant refers to chlorofluorocarbons or hydrocarbons including but not limited to trichlorofluoromethane, dichlorodifluoromethane, chlorodifluoromethane and dichlorotetrafluoroethane.
  • Optimal concentrations of the counterion of choice, decane sodium sulfonate is 2 mg/ml. At this concentration, the equilibrium solubility of the LHRH analog in appropriate cosolvent mixtures of ethyl alcohol and dichlorodifluoromethane is about 20 mg/ml. However, a formulation containing 10 mg/ml of leuprolide appears to possess all desired physical characteristics of a satisfactory/stable aerosol.
  • lipophilic counterions also significantly improve the solubility of LHRH analogs in a propellant-water-ethanol cosolvent system.
  • the most preferred counterions are: alkyl sulfonates followed by palmitates, dioctylsulfosuccinates, stearates and salicylates.
  • a solution aerosol containing approximately 25.0% w/w ethyl alcohol, 1.3% w/w sorbitan monooleate, 0.2% w/w decane sulfonic acid (sodium salt), 3.5% w/w water, 1.0% leuprolide acetate, and 69% w/w dichlorodifluoromethane is a preferred formulation for a leuprolide solution aerosol product.
  • a solution aerosol containing approximately 20.0% w/w ethyl alcohol, 1.3% w/w/ sorbitan monoleate, 0.2% w/w decane sulfonic acid (sodium salt), 1.8% w/w water, 1.0% leuprolide acetate, and 75.7% w/w dichlorodifluoromethane. Both formulations have good spray characteristics and satisfactory physical and chemical stability.
  • compositions of the invention can be prepared by cold filling or pressure filling.
  • Cold filling comprises the steps as follows:
  • Pressure filling comprises the steps as follows:
  • a preferred suspension aerosol contains approximately 10% w/w trichlorofluoromethane, 3% w/w sorbitan trioleate, 1.0% w/w leuprolide acetate, and 86% w/w dichlorodifluoromethane.
  • This formulation has good spray characteristics and has satisfactory physical and chemical stability.
  • This formulation can be prepared as follows:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Reproductive Health (AREA)
  • Otolaryngology (AREA)
  • Endocrinology (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Saccharide Compounds (AREA)
  • Extraction Or Liquid Replacement (AREA)
  • Seasonings (AREA)
  • Cosmetics (AREA)
EP87117226A 1986-11-25 1987-11-23 Compositions d'analogue de LHRH Expired - Lifetime EP0275404B1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP92111535A EP0510731B1 (fr) 1986-11-25 1987-11-23 Formulations analogues de LH-RH
AT87117226T ATE88341T1 (de) 1986-11-25 1987-11-23 Zusammensetzungen enthaltend lhrh-analoga.
GR960401850T GR3020482T3 (en) 1986-11-25 1996-07-09 LHRH Analog formulations

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US06/934,874 US4851211A (en) 1986-11-25 1986-11-25 LHRH analog formulations
US934874 1986-11-25
US114359 1987-11-04
US07/114,359 US4897256A (en) 1986-11-25 1987-11-04 LHRH analog formulations

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP92111535.8 Division-Into 1987-11-23

Publications (2)

Publication Number Publication Date
EP0275404A1 true EP0275404A1 (fr) 1988-07-27
EP0275404B1 EP0275404B1 (fr) 1993-04-21

Family

ID=26812097

Family Applications (2)

Application Number Title Priority Date Filing Date
EP87117226A Expired - Lifetime EP0275404B1 (fr) 1986-11-25 1987-11-23 Compositions d'analogue de LHRH
EP92111535A Expired - Lifetime EP0510731B1 (fr) 1986-11-25 1987-11-23 Formulations analogues de LH-RH

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP92111535A Expired - Lifetime EP0510731B1 (fr) 1986-11-25 1987-11-23 Formulations analogues de LH-RH

Country Status (7)

Country Link
US (1) US4897256A (fr)
EP (2) EP0275404B1 (fr)
JP (1) JP2533586B2 (fr)
AT (1) ATE137963T1 (fr)
CA (1) CA1300009C (fr)
DE (2) DE3751811T2 (fr)
ES (2) ES2040727T3 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5605674A (en) * 1988-12-06 1997-02-25 Riker Laboratories, Inc. Medicinal aerosol formulations
US5766573A (en) * 1988-12-06 1998-06-16 Riker Laboratories, Inc. Medicinal aerosol formulations
US5770559A (en) * 1992-10-14 1998-06-23 The Regents Of The University Of Colorado Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same
EP0995434A2 (fr) * 1988-12-06 2000-04-26 Riker Laboratories, Inc. Formulations d'aérosols à usage médical
EP1406592A2 (fr) * 2001-07-18 2004-04-14 Aeropharm Technology Incorporated Formulation d'aerosol medical a paire sel/ion

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4994439A (en) * 1989-01-19 1991-02-19 California Biotechnology Inc. Transmembrane formulations for drug administration
US5011678A (en) * 1989-02-01 1991-04-30 California Biotechnology Inc. Composition and method for administration of pharmaceutically active substances
JPH09501418A (ja) * 1993-07-19 1997-02-10 アムジエン・インコーポレーテツド エアゾル化タンパク質の安定化
US5711934A (en) * 1994-04-11 1998-01-27 Abbott Laboratories Process for the continuous milling of aerosol pharmaceutical formulations in aerosol propellants
US5677184A (en) * 1994-04-19 1997-10-14 Takeda Chemical Industries, Ltd. CHO cells that express human LH-RH receptor
US5635159A (en) * 1994-08-26 1997-06-03 Abbott Laboratories Aerosol drug formulations containing polyglycolyzed glycerides
US7572252B1 (en) * 1995-06-07 2009-08-11 Alza Corporation Electrotransport agent delivery method and apparatus
US5635161A (en) * 1995-06-07 1997-06-03 Abbott Laboratories Aerosol drug formulations containing vegetable oils
US5874064A (en) * 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US6652837B1 (en) 1996-05-24 2003-11-25 Massachusetts Institute Of Technology Preparation of novel particles for inhalation
BR9710130A (pt) * 1996-07-03 1999-08-10 Alza Corp Formulações de peptídeos próticas não-aquosas
US5932547A (en) * 1996-07-03 1999-08-03 Alza Corporation Non-aqueous polar aprotic peptide formulations
US5981489A (en) * 1996-07-18 1999-11-09 Alza Corporation Non-aqueous protic peptide formulations
CA2277801C (fr) * 1997-01-16 2002-10-15 Massachusetts Institute Of Technology Preparation de particules pour inhalation
EP1498115A1 (fr) * 1997-01-16 2005-01-19 Massachusetts Institute Of Technology Préparation de particules pour inhalation
US6099851A (en) * 1998-06-02 2000-08-08 Weisman; Kenneth M. Therapeutic uses of leuprolide acetate
US7678364B2 (en) 1999-08-25 2010-03-16 Alkermes, Inc. Particles for inhalation having sustained release properties
US6749835B1 (en) 1999-08-25 2004-06-15 Advanced Inhalation Research, Inc. Formulation for spray-drying large porous particles
DE10043509A1 (de) * 2000-09-01 2002-03-14 Asta Medica Ag Feste Peptidzubereitungen für die Inhalation und deren Herstellung
AU2002230993B2 (en) 2000-12-29 2006-02-02 Alkermes, Inc. Particles for inhalation having sustained release properties
DE10214031A1 (de) * 2002-03-27 2004-02-19 Pharmatech Gmbh Verfahren zur Herstellung und Anwendung von Mikro- und Nanoteilchen durch aufbauende Mikronisation
US7709525B2 (en) 2003-02-27 2010-05-04 Wisconsin Alumni Research Foundation Chroman-derived anti-androgens for treatment of androgen-mediated disorders
WO2004110603A2 (fr) * 2003-06-03 2004-12-23 Ferro Corporation Procede de preparation de particules a partir d'emulsions de solution dans un fluide supercritique ou un gaz comprime
WO2005077339A1 (fr) * 2004-02-10 2005-08-25 E.I. Dupont De Nemours And Company Procede de preparation de sol stable constitue d'ingredients pharmaceutiques et d'hydrofluorocarbone consistant a melanger ledit sol, puis a le transferer dans un contenant
WO2005106350A2 (fr) * 2004-04-23 2005-11-10 Philip Morris Usa Inc. Generateurs d'aerosol et procede de production d'aerosols

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3560607A (en) * 1962-11-30 1971-02-02 Fisons Pharmaceuticals Ltd Aerosol formulations of finely divided solid medicaments with anionic surface-active agents
FR2205307A1 (en) * 1972-11-04 1974-05-31 Hoechst Ag Luteal hormone-releasing hormone prepns - for treatment of hypothalamus insufficiency by intranasal admin.
EP0111841A1 (fr) * 1982-12-10 1984-06-27 Syntex (U.S.A.) Inc. Préparations de LHRH pour l'administration nasale
US4476116A (en) * 1982-12-10 1984-10-09 Syntex (U.S.A.) Inc. Polypeptides/chelating agent nasal compositions having enhanced peptide absorption

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US3898329A (en) * 1971-09-17 1975-08-05 Sami I Said Vasoactive intestinal peptide, composition and method
GB1454105A (en) * 1972-11-04 1976-10-27 Hoechst Ag Preparation containing luteinizing hormone-releasing factor
FR2320107A1 (fr) * 1975-08-05 1977-03-04 Anvar Nouveaux adjuvants immunologiques, procede pour leur obtention et compositions les contenant
US4405598A (en) * 1976-01-30 1983-09-20 Fisons, Limited Composition for treating asthma
DE2750090A1 (de) * 1976-11-19 1978-06-01 Sandoz Ag Neue verabreichungsformen fuer organische verbindungen
US4438029A (en) * 1978-01-19 1984-03-20 Research Corporation Synthetic peptides
JPS5819669B2 (ja) * 1978-10-28 1983-04-19 白井松新薬株式会社 新規生理活性ペプチド化合物及びその製造法
JPS57188526A (en) * 1981-05-14 1982-11-19 Takeda Chem Ind Ltd Peptide-containing pharmaceutical preparation
US4481191A (en) * 1983-03-30 1984-11-06 The Regents Of The University Of California Method for controlling blood pressure
GB8322178D0 (en) * 1983-08-17 1983-09-21 Sterwin Ag Preparing aerosol compositions

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3560607A (en) * 1962-11-30 1971-02-02 Fisons Pharmaceuticals Ltd Aerosol formulations of finely divided solid medicaments with anionic surface-active agents
FR2205307A1 (en) * 1972-11-04 1974-05-31 Hoechst Ag Luteal hormone-releasing hormone prepns - for treatment of hypothalamus insufficiency by intranasal admin.
EP0111841A1 (fr) * 1982-12-10 1984-06-27 Syntex (U.S.A.) Inc. Préparations de LHRH pour l'administration nasale
US4476116A (en) * 1982-12-10 1984-10-09 Syntex (U.S.A.) Inc. Polypeptides/chelating agent nasal compositions having enhanced peptide absorption

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 71, no. 12, December 1982, pages 1367-1371, American Pharmaceutical Association, US; H. OKADA et al.: "Vaginal absorption of a potent luteinizing hormone-releasing hormone analog (leuprolide) in rats I: absorption by various routes and absorption enhancement" *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5776434A (en) * 1988-12-06 1998-07-07 Riker Laboratories, Inc. Medicinal aerosol formulations
US5766573A (en) * 1988-12-06 1998-06-16 Riker Laboratories, Inc. Medicinal aerosol formulations
US5681545A (en) * 1988-12-06 1997-10-28 Riker Laboratories, Inc. Medicinal aerosol formulations
US5683677A (en) * 1988-12-06 1997-11-04 Riker Laboratories, Inc. Medicinal aerosol formulations
US5605674A (en) * 1988-12-06 1997-02-25 Riker Laboratories, Inc. Medicinal aerosol formulations
US5720940A (en) * 1988-12-06 1998-02-24 Riker Laboratories, Inc. Medicinal aerosol formulations
US5674473A (en) * 1988-12-06 1997-10-07 Riker Laboratories, Inc. Medicinal aerosol formulations
EP0499344B2 (fr) † 1988-12-06 2009-09-09 3M Innovative Properties Company Formulations d'aérosols à usage médical comprenant salbutamol
US5695743A (en) * 1988-12-06 1997-12-09 Riker Laboratories, Inc. Medicinal aerosol formulations
EP0995434A3 (fr) * 1988-12-06 2003-11-26 Riker Laboratories, Inc. Formulations d'aérosols à usage médical
EP0995434A2 (fr) * 1988-12-06 2000-04-26 Riker Laboratories, Inc. Formulations d'aérosols à usage médical
US6352684B1 (en) 1988-12-06 2002-03-05 Riker Laboratories Inc. CRC-free medicinal aerosol formulations of 1,1,1,2-tetrafluoroethane (134A) with polar adjuvant
US5981474A (en) * 1992-10-14 1999-11-09 University Technology Corporation Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same
US5770559A (en) * 1992-10-14 1998-06-23 The Regents Of The University Of Colorado Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same
EP1406592A2 (fr) * 2001-07-18 2004-04-14 Aeropharm Technology Incorporated Formulation d'aerosol medical a paire sel/ion
EP1406592A4 (fr) * 2001-07-18 2010-03-17 Aeropharm Technology Inc Formulation d'aerosol medical a paire sel/ion

Also Published As

Publication number Publication date
DE3751811T2 (de) 1996-11-28
ES2040727T3 (es) 1993-11-01
EP0275404B1 (fr) 1993-04-21
DE3785570T2 (de) 1993-11-18
EP0510731A1 (fr) 1992-10-28
DE3751811D1 (de) 1996-06-20
JPS63211237A (ja) 1988-09-02
CA1300009C (fr) 1992-05-05
EP0510731B1 (fr) 1996-05-15
ATE137963T1 (de) 1996-06-15
JP2533586B2 (ja) 1996-09-11
ES2089301T3 (es) 1996-10-01
DE3785570D1 (de) 1993-05-27
US4897256A (en) 1990-01-30

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